The present invention relates to novel substituted cinnamyl-2,3-dihydrobenzofuran and analogs useful as anti-inflammatory agents useful as topical anti-inflammatory agents. A number of cinnamylphenols have been known to have antibiotic activities. For example, those disclosed in U.S. Pat. Nos. 3,745,222; 3,775,540; 3,777,037; 3,865,748; 3,936,393; 3,951,820; and 4,105,698. However, these patents did not disclose the novel compounds of the present invention especially those compounds related to substituted cinnamyl-2,3-dihydrobenzofurans or its analogs, nor did they disclose the newly discovered topical anti-inflammatory activity of these compounds.
We have found that the novel compounds are active in vitro in both the peritoneal macrophage assay and the polymorphonuclear leukocyte assay. We have also found that these compounds are active in vivo in the topical mouse ear assay and the U.V. erythema assay for anti-inflammatory agents. However, these compounds tend to be inactivated in vivo and thereby are devoid of any signficant systemic effects.
Recent studies demonstrated that macrophages participate in the development and progression of chronic inflammatory diseases such as rheumatoid arthritis. During the progression of inflammatory conditions, there is generally an appearance and/or presence of macrophages and lymphocytes, especially macrophages and polymorphonuclear leukocytes. Macrophages are known to secrete various products in response to inflammatory stimuli. For example:
(1) Neutral proteinases--the destructive peptide bond cleaving enzyme which has been shown to be directly involved in rheumatoid cartilage destruction; and PA1 (2) Prostaglandins (PG) (e.g., E.sub.2 and I.sub.2 by mouse peritoneal macrophages) and other arachidonic acid derivatives derived from both the cyclooxygenase and the lipoxygenase pathways. PA1 (a) hydroxyloweralkyl; PA1 (b) lower alkanoyl; PA1 (c) CN; PA1 (d) halo; PA1 (e) mercaptoloweralkyl especially mercapto C.sub.1-6 alkyl such as --CH.sub.2 SR.sup.2 where R.sup.2 represents H or loweralkyl, PA1 (f) lower alkylthio especially C.sub.1-6 alkylthio such as --SCH.sub.3 ; PA1 (g) lower haloalkyl; PA1 (h) --COOR.sup.2 ; PA1 (i) hydroxycarbonylloweralkyl especially hydroxycarbonyl-C.sub.1-6 alkyl such as --CH.sub.2 COOH; PA1 (j) lower alkoxycarbonylloweralkyl especially C.sub.1-6 alkoxycarbonyl C.sub.1-6 alkyl such as --CH.sub.2 COO t--Bu; PA1 (k) haloloweralkanoyl especially halo C.sub.1-6 alkanoyl such as trifluoroacetyl; PA1 (a) phenyl substituted with (R.sup.1).sub.q wherein when there are more than one R.sup.1 (q 1) R.sup.1 can be the same or different from each other and is PA1 (b) unsubstituted or substituted heteroaryl, for example: PA1 (a) COOR.sup.2 ; PA1 (b) loweralkoxy; PA1 (c) haloloweralkylcarbonyl especially haloC.sub.1-6 alkylcarbonyl such as CF.sub.3 CO--; PA1 (d) halo; PA1 (e) loweralkanoyl especially acetyl; PA1 (f) lowerhaloalkyl especially trifluoromethyl; PA1 (g) hydroxyloweralkyl eg. --CH.sub.2 OH; or PA1 (h) cyano; PA1 (a) hydrogen; PA1 (b) loweralkoxy; PA1 (c) halo; PA1 (d) lowerhaloalkyl, PA1 (e) loweralkanoyl; PA1 (f) hydroxyloweralkyl; or PA1 (q) CN;
These archidonic acid oxygenation products have been identified as the critical mediators of various inflammatory conditions.
Interruption of these pathways by enzyme inhibition has been explored for effective therapy. For example, non-steroidal anti-inflammatory drugs (NSAID) such as aspirin, indomethacin and diflunisal are known cyclooxygenase inhibitors which inhibit the process wherein arachidonic acid is oxygenated via cyclooxygenase to prostaglandins and thromboxanes.
Recently, it has been observed that certain leukotrienes are responsible for diseases related to immediate hypersensitivity reactions such as human asthma, allergic disorders, and skin diseases. In addition, certain leukotrienes and derivatives thereof are believed to play an important role in causing inflammation (B. Samuelsson, Science, 220, 568 (1983); D. Bailey et al, Ann. Rpts. Med. Chem., 17, 203 (1982)).
Conditions involving elevated intraocular pressures which are too high for normal function may result in irreversible loss of visual function. For example, glaucoma, if untreated, may lead to ocular hypertension, inflammation, and eventually blindness.
To be an effective and acceptable topical agent, for treating inflammation in the eye, such as that caused by glaucoma or other eye diseases, the drug must not only penetrate the ophthalmic tissues to reach the active sites within the eye, but it must also be devoid of those side effects including irritation, allergic reaction and the like which would militate against long term administration.
Accordingly, pharmacological agents which are capable of inhibiting the formation of, the release of a mediator from, or the function of macrophages or polymorphonuclear leukocytes may also be effective agents in the treatment of various inflammatory conditions, e.g., pain, fever, rheumatoid arthritis, osteoarthritis, bronchial inflammation, inflammatory bowel disease, asthma, allergic disorders, skin diseases, cardiovascular disorders, glaucoma, emphysema, acute respiratory distress syndrome, spondylitis, lupus, gout, psoriasis, and other prostaglandis and/or leukotriene mediated diseases.
Regarding the topical mouse ear assay, it has been previously established that classical nonsteroidal anti-inflammatory agents such as indomethacin and steroidal anti-inflammatory agents such as dexamethasone are active in this assay.
With respect to the U.V. erythema assay, it has been shown previously that the U.V. erythema condition is partially the result of a local release of prostaglandins derived oxidatively from arachiodonic acid by the action of PG synthetases, e.g., cyclooxygenase. Therefore, pharmacological agents which inhibit the erythema are generally considered to be active topical anti-inflammatory agents.
Furthermore, anti-inflammatory agents which are not significantly systemically active are advantageous in the sense that they are not subject to the adverse effects, e.g., gastrointestinal ulcerations and bleeding that often plagued users of systemic NSAIDs (non-steroidal anti-inflammatory agents). Accordingly, an object of this invention is to provide novel substituted cinnamyl-2,3-dihydrobenzofuran derivatives and analogs as dual enzyme inhibitors of cyclooxygenase and lipoxygenase and particularly as topical anti-inflammatory agents. These agents are especially useful in the treatment of, among others, dermal inflammatory conditions and prusitus such as sunburn, erythema, eczema, contact dermatitis, allergic dermatitis, eye inflammation caused by glaucoma, and psoriasis. They are also useful for topical application to prevent periodontal diseases.
Another object of this invention is to provide appropriate processes for the preparation of the subject novel compounds.
Still a further object of the present invention is to provide a pharmaceutically acceptable composition containing an effective amount of the active compound for the treatment of various dermatological inflammatory conditions.
Finally, it is the ultimate object of this invention to develop a method of treating dermal inflammation via the administration of a therapeutically effective amount of the novel compounds or pharmaceutically acceptable compositions thereof to a mammalian species in need of such treatment.